title: In vitro and in vivo profiling of fadolmidine, a novel potent alpha(2)-adrenoceptor agonist with local mode of action.
abstract: Alpha2-adrenergic receptors (alpha2-adrenoceptors) mediate various physiological actions of endogenous catecholamines in the central and peripheral nervous systems being involved in alertness, heart rate regulation, vasomotor control and nociceptive processing. In the present study, the pharmacological profile of a novel alpha2-adrenoceptor agonist, fadolmidine, was studied in various in vitro and in vivo assays and compared to the well characterised alpha2-adrenoceptor agonist, dexmedetomidine. Fadolmidine displayed high affinity and full agonist efficacy at all three human alpha2-adrenoceptor subtypes (A, B and C) in transfected CHO cells with EC50 values (nM) of 0.4, 4.9 and 0.5, respectively. Fadolmidine inhibited also electrically evoked contractions in rat vas deferens demonstrating the activation of rodent presynaptic alpha2D-adrenoceptors with an EC50 value of 6.4 nM. Moreover, fadolmidine was a full agonist at human alpha1A-adrenoreceptor (EC50 value 22 nM) and alpha1B-adrenoreceptor (EC50 value 3.4 nM) in human LNCaP cells and transfected HEK cells, respectively. Agonism at the alpha1-adrenoceptor was also observed in rat vas deferens preparations although at lower potency (EC50 value 5.6 microM). Fadolmidine demonstrated potent alpha2-adrenoceptor agonist activity also in vivo by inhibiting electrically induced tachycardia in pithed rats and increasing mean arterial pressure in anaesthetised rats. However, after systemic administration, fadolmidine had considerably weaker CNS-mediated effects (mydriasis and sedation) compared to dexmedetomidine possibly due to limited penetration through the blood brain barrier by fadolmidine. In a conclusion, fadolmidine is a potent full agonist at all three alpha2-adrenoceptor subtypes with a pharmacological profile compatible with a therapeutic value e.g. after spinal administration.
authors.affiliation: Orion Corporation Orion Pharma, Nonclinical R&D, P.O. Box 425, FI-20101 Turku, Finland. jyrki.lehtimaki@orionpharma.com
authors.forename: Jyrki
authors.initials: J
authors.lastname: Lehtimäki
authors.forename: Tiina
authors.initials: T
authors.lastname: Leino
authors.forename: Ari
authors.initials: A
authors.lastname: Koivisto
authors.forename: Timo
authors.initials: T
authors.lastname: Viitamaa
authors.forename: Tarja
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Antti
authors.initials: A
authors.lastname: Haapalinna
authors.forename: Katja
authors.initials: K
authors.lastname: Kuokkanen
authors.forename: Raimo
authors.initials: R
authors.lastname: Virtanen
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D020927:Dexmedetomidine / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1; D014162:Transfection; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
chemical_list: C547713:ADRA1A protein, human; C547716:ADRA1B protein, human; C547714:Adra1a protein, mouse; C547715:Adra1a protein, rat; C547717:Adra1b protein, mouse; C547718:Adra1b protein, rat; D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D007189:Indans; D018340:Receptors, Adrenergic, alpha-1; D020927:Dexmedetomidine; C400294:radolmidine